The present invention relates to certain pyrazolo-triazolo-pyrimidine, triazolo-triazolo-pyrimidine and imidazolo-triazolo-pyrimidine derivatives and their use in the practice of medicine as modulators of adenosine A3 receptors.
Three major classes of adenosine receptors, classified as A1, A2, and A3, have been characterized pharmacologically. A1 receptors are coupled to the inhibition of adenylate cyclase through Gi proteins and have also been shown to couple to other second messenger systems, including inhibition or stimulation of phosphoinositol turnover and activation of ion channels. A2 receptors are further divided into two subtypes, A2A and A2B, at which adenosine agonists activate adenylate cyclase with high and low affinity, respectively. The A3 receptor sequence was first identified in a rat testes cDNA library, and this sequence, later cloned by homology to other G-protein coupled receptors from a rat brain cDNA library, was shown to correspond to a novel, functional adenosine receptor.
The discovery of the A3 receptor has opened new therapeutic vistas in the purine field. In particular, the A3 receptor mediates processes of inflammation, hypotension, and mast cell degranulation. This receptor apparently also has a role in the central nervous system. The A3 selective agonist IB-MECA induces behavioral depression and upon chronic administration protects against cerebral ischemia. A3 selective agonists at high concentrations were also found to induce apoptosis in HL-60 human leukemia cells. These and other findings have made the A3 receptor a promising therapeutic target. Selective antagonists for the A3 receptor are sought as potential antiinflammatory or possibly antiischemic agents in the brain.
Mast cell degranulation is a component of myocardial reperfusion injury, hypersensitivity reactions (asthma, allergic rhinitis, and urticaria), ischemic bowel disease, autoimmune inflammation, and atopic dermatitis. Selective A3 adenosine receptor antagonists can be used to treat or prevent these diseases and pathologic effects that result from mast cell degranulation.
For example, A3 antagonists have been under development as antiasthmatic, antidepressant, antiarrhythmic, renal protective, antiparkinson and cognitive enhancing drugs.
Further investigation has identified A3 receptors in a number of human cancers, including pancreatic cancer, colon cancer, breast cancer, lung cancer and human malignant melanoma. Surprisingly, A3 receptors are found at higher concentrations in the cancerous cells as compared to normal healthy tissue.
Although others have studied the apoptosis induced effect of A3 agonists, inventors have also demonstrated success in using A3 antagonists to induce apoptosis in human cancers. The use of A3 antagonists with selectivity allows targeting of the cancer cells for apoptosis thereby reducing anticipated side effects in treatment of patients.
It is therefore an object of the present invention to provide compounds and methods of preparation and use thereof, which are antagonists or partial antagonists of the adenosine A3 receptor.